Transactive Response DNA-Binding Protein (TARDBP/TDP-43) Regulates Cell Permissivity to HIV-1 Infection by Acting on HDAC6

Abstract

The transactive response DNA-binding protein (TARDBP/TDP-43) influences the processing of diverse transcripts, including that of histone deacetylase 6 (HDAC6). Here, we assessed TDP-43 activity in terms of regulating CD4+ T-cell permissivity to HIV-1 infection. We observed that overexpression of wt-TDP-43 increased both mRNA and protein levels of HDAC6, resulting in impaired HIV-1 infection independently of the viral envelope glycoprotein complex (Env) tropism. Consistently, using an HIV-1 Env-mediated cell-to-cell fusion model, the overexpression of TDP-43 levels negatively affected viral Env fusion capacity. Silencing of endogenous TDP-43 significantly decreased HDAC6 levels and increased the fusogenic and infection activities of the HIV-1 Env. Using pseudovirus bearing primary viral Envs from HIV-1 individuals, overexpression of wt-TDP-43 strongly reduced the infection activity of Envs from viremic non-progressors (VNP) and rapid progressors (RP) patients down to the levels of the inefficient HIV-1 Envs observed in long-term non-progressor elite controllers (LTNP-EC). On the contrary, silencing endogenous TDP-43 significantly favored the infectivity of primary Envs from VNP and RP individuals, and notably increased the infection of those from LTNP-EC. Taken together, our results indicate that TDP-43 shapes cell permissivity to HIV-1 infection, affecting viral Env fusion and infection capacities by altering the HDAC6 levels and associated tubulin-deacetylase anti-HIV-1 activity.

Contribution of the HIV-1 Envelope Glycoprotein to AIDS Pathogenesis and Clinical Progression

“…The investigation of the HIV-1 env /Env functions was undertaken analyzing viruses from HIV-1 individuals with different clinical phenotypes: LTNP-ECs, viremic non-progressors, progressors and rapid progressors (RPs) [ 26 , 44 , 70 , 71 , 72 , 73 , 83 , 121 , 122 , 123 , 124 , 125 , 126 , 127 ]. In our initial studies, we focused on LTNP individuals infected for long periods of time (i.e., more than 10 years and with more than 25–30 years of clinical follow-up) [ 26 , 44 , 70 , 72 , 121 , 127 ]. The isolated viral env sequences (full-length viral env ) from infected individuals were cloned into expression plasmids ( Figure 2 a).…”

“…In contrast to the Envs from the LTNP-EC subjects, the viruses from the progressor individuals (viremic and progressors) showed the opposite properties, with a good affinity for CD4, cell fusion and viral transfer [ 70 , 72 , 121 , 127 ]. Therefore, functional HIV-1 Envs are associated with infectious virus and cytopathic activity [ 71 , 72 ], which characterize viremic and progressor/RP clinical outcomes [ 70 , 72 , 121 , 127 ] ( Figure 3 and Figure 4 ). Functional HIV-1 Envs favor the accumulation of mutations that could result in function gains of the Envs and the evasion from immune responses ( Figure 3 and Figure 4 ).…”

“…These processes are summarized in Figure 3 . In the characterization of these HIV-1 Envs properties, we analyzed HIV-1 Envs from viremic non-progressors (VNPs), progressors and rapid progressors (RPs) patients [ 44 , 70 , 72 , 73 , 121 , 127 ]. The phenotypic characterization of the Envs from HIV-1 progressors ( Figure 3 and Figure 4 ) indicated higher replication capacity for these HIV-1 viruses when compared with HIV-1 Envs of viruses from the LTNP-EC cluster [ 121 ].…”

“…Furthermore, in the late AIDS phase of chronic infection in RPs, uncontrolled HIV-1 replication occurs together with the selection of the fittest variants [ 148 ]. Therefore, functional HIV-1 Envs are directly associated with infectious viruses of viremic and progressors patients in which HIV-1 infection evolves [ 70 , 71 , 72 , 127 ] ( Figure 1 , Figure 3 and Figure 4 ).…”

“…This efficient viral function of the HIV-1 Env, in a CD4 dependent manner, allows the virus to overcome cell barriers that limit HIV-1 Env-mediated pore fusion formation, viral entry to the cell, infection and replication ( Figure 3 a). A key restriction factor for HIV-1 infection that we characterized is the cytoplasmic enzyme HDAC6 (histone deacetylase 6) [ 70 , 71 , 72 , 126 , 127 , 142 , 205 ], and more recently the transactive response of the DNA-binding protein (TARDBP or TDP-43) together with HDAC6 (i.e., the TDP-43/HDAC6 axis) [ 127 ]. An increase in the expression of functional TDP-43 concomitantly enhances the levels of mRNA and protein of HDAC6, leading to a diminution of the activity of functional HIV-1 Envs from viruses of VNP and RP individuals, reaching the levels of the inefficient Env from LTNP-EC individuals [ 127 ].…”